Monday, April 23, 2007

A human microbiome program?

I am currently attending a workshop sponsored by NIH in which the participants are discussing whether there should be a Human Microbiome Project, and if so, what that should mean.

First, what is generally meant by the "Microbiome." In essence the humn microbiome is the sum collection of all the microbes found in or on people. The human microbiome has become an important research field because the microbes that live in and among us play critical roles in human disease and health. An important aspect of this is the idea that microbes can be and are beneficial. For example, in the gut the normal microbes help with digestion and nutrient absorption as well as protect from infection. In addition, a variety of diseases (e.g., IBD, Krohns) seem likely to be caused by disruption in the normal microbial flora. In general, it seems likely that other ailments, like autoimmune diseases, allergies, etc will be found to have a connection to disruptions in the beneficial microbes that live among us.

Because of the importance of beneficial / commensal microbes in human biology, there have been growing efforts to characterize the microbes in various body locations - gut, mouth, lungs, skin, etc. But the efforts so far have simply given a tantalizing taste of how interesting and important these microbes are. So here comes this meeting. Organized by NIH (specifically, Francis Collins at NHGRI), this workshop is geared to discuss the possibility that studies of the human microbiome will be included in the next list of "NIH Roadmap" programs. More on the NIH Roadmap some other time.

Basically, the general idea is - do we need an big scale, organized program to tackle the human microbiome.? To get us in the mood, we had talks by many of the pioneers/leaders in the field (e.g., David Relman, Jeff Gordon, Jim Tiedje) as well as discussion of the NIH Roadmap program. I personally did not need any convincing but it was good to hear some of the ideas presented. In the end, I think there is no doubt that a large scale Human Microbiome Program is needed and would be very beneficial.

One of the reasons that an organized effort is needed is that studies of the human micribome are difficult. Reasons for this include:

1. Many of the microbes in the human system have not, and maybe cannot, be grown in isolation in the lab

2. The key features of the microbiome are determined by by populations of microbes and thus even if a representative of a species could be grown in the lab, it would not represent all the diversity in the population.

3. The best way to sample the populations is via "metagenomic" sequencing which involves isolating DNA and sequencing it directly without culturing.

4. Many of the important sites contain hundreds of species each with significant variation within species.

5. There likely will be ENORMOUS variation in and among people. Within a person, there will be variation over time as well as great variation in different sites. On top of that there will be great variation between people.

Given these and other complications, it seems a no brainer there is a need for a coordinated project to gather background information about the human microbiome that would then be useful to researchers, much like the human genome was useful to many researchers. So what would such a project do? Here are some possibilities

1. Sequence many "reference genomes." By reference genomes here I mean genomes of cultured isolates that are closely related to organisms known in various human locations.

2. Do metagenomic sequencing of a variety of human mcirobiome samples.

3. Conduct large scale human microbiome diversity studies. This could involve rRNA PCR surveys as well as some amount of genome sequencing.

4. Develop the computational tools needed to analyze the massive amounts of data that will come out.

5. Encourage the development of new methods to aid in studies of the microbiome.

So today I guess we will be discussing what specific things are needed in more detail. But again, even though I do not really work on human microbiome projects much, I think it is pretty clear that the time is right for a Human Microbiome Program. And importantly, the methods and tools and discoveries that could come from this will be of use in all studies of microbes in the environment.

6 comments:

Last year, I did my qualifying exam proposal on metagenomic sequencing of the human gut. It's a ridiculously interesting problem because the field is so wide-open at the moment. There are only a few early papers and they're so limted in scope that they don't really tell us a whole lot. (Gill, et al is the best one I've seen thus far" http://www.sciencemag.org/cgi/content/abstract/312/5778/1355)

The scale of the problem is pretty staggering, though - estimates say there may be 100x more genes in our metagenome than there are in our actual genome. Sorting out the signal from the noise is going to be a bioinformaticist's dream (or nightmare, depending on your perspective)

Very cool and very complex. Hope it gets off the ground soon. The results that will come out, scientists of all stripes will be pouring over for years on end. Would I be correct in estimating that microbes gained significantly more surface area on which to grow by the presence of multicellular organisms?

I would like to add one more "pro" to your list: having the human genome sequenced, it would be the first complete eukariotic-bacterial metagenome to be achieved, which would provide a great space to asses evolutionary and ecological problems.

However, I'm not sure it would be economically achievable and feasible in the sense of human work, since a good sampling would translate in an enormous sequencing effort.

Oooh, hell yeah, we need this. And not just one--many. Dozens. Hundreds when we can get up to it. There are so many interesting areas of investigation involving health and our "normal flora" right now that this kind of research is imperative.